Abstract Recent clinical trials for Romosozumab, a monoclonal antibody targeting the protein sclerostin, have shown it to be highly effective in reducing fracture risk in patients with osteoporosis. However, cardiovascular side effects have been a major roadblock in FDA approval of the drug and may hinder its adoption in clinical disease management. Although it was originally believed sclerostin was only expressed in the skeleton, recent studies have demonstrated its expression in cardiovascular tissue, cells, and disease. Research correlating circulating sclerostin to cardiovascular disease has been confounding. Very few studies of the mechanism of sclerostin in cardiovascular disease have been published, and none have examined the protein?s role in aortic valve health and disease, despite the protein being discovered in diseased valves. Calcific aortic valve disease (CAVD) is the most common affliction of the cardiac valves and is becoming more prevalent in aging populations. It is a notoriously difficult disease to study and treat, and is responsible for approximately 15,000 deaths per year in North America. Pathogenesis of CAVD is characterized by gradual accumulation of fibrocalcific lesions resulting in reduced compliance and difficulty pumping blood to systemic circulation. Without valve replacement, CAVD can lead to death via heart failure. There is an acute need to unravel the molecular pathophysiology of this disease in order to develop efficacious pharmaceuticals. Preliminary results from our lab indicate sclerostin is necessary in the development of CAVD in a mouse model. Additionally, valve interstitial cells shift to a disease phenotype when treated with the protein in vitro. We hypothesize sclerostin is a driver of CAVD through its stimulation of the RANKL-NF?B signaling pathway leading to fibrosis and dystrophic calcification by activated valve interstitial cells. The goal of this proposal is to better understand the role of sclerostin in CAVD and assess its potential as a pharmacological target. This study presents two primary aims: 1) multiscale molecular characterization of the CAVD phenotype of Sost genetic mutant mice 2) investigation of valve disease in a pre- clinical analogue of sclerostin blocking in post-menopausal osteoporosis. This study will be the first to identify the molecular mechanism of sclerostin in aortic valve health and disease. Intensive analysis of genetic and pharmacological reduction of sclerostin signaling will provide insight into the side effects observed in osteoporosis treatment as well as potential for treatment of CAVD.